The Wredenberg Lab

Stockholm

About the lab

We are a young research group at the Division of Molecular Metabolism at the Karolinska Institute, working on various aspects of mitochondrial biology. Mitochondria form an integral part of cellular metabolism with many metabolic pathways relying on or passing through mitochondria. Dysfunction of any of these metabolic pathways can have significant affects on human health. We are interested in understanding the connections between energy metabolism and cell function and how disturbances in this network affects an individual’s health. For this, we use a combination of model systems, ranging from the fruit fly, Drosophila melanogaster, to patient-derived iPS cells, for detailed molecular and metabolic characterisation.

Anna Wredenberg recently received an ERC start-up grant. She is a Ragnar Söderberg fellow in Medicine and an MD at the Centre for inherited metabolic diseases at the Karolinska University Hospital. The centre is a specialised clinic for the diagnosis of inherited metabolic diseases and performs a range of molecular, bioenergetic and metabolic investigations on patients from all over Sweden. Modern diagnostic tools have dramatically increased our understanding of these diseases, and provide a unique opportunity to identify the molecular mechanisms of metabolic derangements. We work in close collaboration with the clinic to diagnose, validate and understand metabolic diseases.

Research

Mitochondria form a dynamic network in almost every eukaryotic cell, rapidly responding to a variety of cellular demands. Although mitochondria are predominantly known to perform the final steps of aerobic energy metabolism, they are essential for other processes as diverse as steroid and lipid metabolism, iron-sulphur cluster formation, calcium buffering, reactive oxygen species (ROS) formation or apoptosis. Mitochondria are therefore seen as forming a central hub for cellular metabolism and understanding their role within the remaining metabolic network is essential for a variety of complex human diseases. For instance, mitochondrial dysfunction can be observed in several neurodegenerations, heart disease, diabetes mellitus and has been suggested to be a major contributor to the natural ageing process.

For this we use a range of model systems, including genetically modified fruit flies, to broaden our understanding of the molecular interactions that affect mitochondrial metabolism, both in health and disease.
Our research tries to identify the molecular consequences of metabolic derangements, by understanding how mitochondria function within the metabolic system. We also have a special focus on understanding the turnover of mitochondrial transcripts, and how changes in mitochondrial gene expression is regulated on a post-transcriptional level.

Mitochondria contain their own DNA, which is transcribed and translated within the mitochondrial network. Although several factors involved in mitochondrial RNA metabolism have already been identified, the mechanisms of what regulates their involvement in processing, modifying or degrading are still very sparse. With the help of genetically modified fruit fly models we study the molecular mechanisms that determine mitochondrial RNA metabolism and how they interact with mitochondrial translation.

Mitochondrial dysfunction can result in a range of rare inborn errors of metabolism (IEM), but has also been associated with a range of common diseases including cancer, heart failure, neurodegeneration, diabetes mellitus and natural ageing. The complexity and lack of understanding leaves many patients with IEMs undiagnosed. We work in close collaboration with the centre for inherited metabolic diseases at the Karolinska University Hospital to functionally validate novel gene variants identified in patients with IEM.

We combine several approaches, including analysing differentiated induced pluripotent stem (iPS) cells or mutation-specific fly models to fully validate novel genetic variants from patients with IEM. By understanding the molecular, bioenergetic and proteomic alterations in IEM, we believe that we will gain a much better understanding of human metabolism in health and disease.